Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.
The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
Organ transplantation has become an established therapy for selected patients with end-stage organ dysfunction. As a result the number of patients referred for transplantation continues to increase thereby exacerbating a chronic donor organ shortage problem and leading to the use of more “marginal” organs that would otherwise have been declined during previous years. However, in addition to the problems of organ rejection, this being the most widely publicized complication of organ transplantation, there occurs another serious complication which often precedes rejection, this being the onset of graft dysfunction. This condition can both lead to failure of the organ and exacerbate immunological rejection of the organ. The incidence of this complication has been exacerbated by virtue of the use of organs which, in previous years, would have been regarded as unsuitable for use as a transplant. Still further, primary graft dysfunction occurs despite significant advances in organ handling, storage and preservation, with an incidence of between 10% and 12% and with an associated risk of mortality at 30 days of between 42% and 63%, making it the leading cause of early death after transplantation (Christie et al. 2005, Am J Respir Crit Care Med 171:1312-1316; Christie et al. 2005, Chest 127:161-165).
Primary graft dysfunction or failure is a form of allograft ischemia-reperfusion injury that typically occurs within 72 hours of transplantation and is exacerbated by acute and chronic conditions that compromise the donor allograft. In the setting of lung transplantation, for example, it is particularly common and is characterised by hypoxemia, substantial alveolar oedema and non-specific alveolar damage, similar to what is characteristic of Acute Respiratory Distress Syndrome (ARDS) (Christie et al. 2005 supra; de Perrot et al. 2003, Am J Respir Crit Care Med 167:490-511). The pathophysiological changes that are associated with lung ischemia-reperfusion are complex and involve time-dependent modulation of various oxidative stress, proinflammatory and prothrombotic pathways that ultimately result in cellular injury and death. In addition to lung, other solid transplant organs including kidney, liver and heart undergo similar ischemia-reperfusion injury related changes in preparation for transplantation that result in the establishment of a proinflammatory state that may be detrimental to graft survival (Boros and Bromberg 2006, Am J Transplant 6:652-658; Jamieson and Friend 2008, Front Biosci 13:221-235; Laskowski et al. 2000, Ann Transplant 5:29-35; van der Woude et al. 2004, J Investig Med 52:323-329).
Lung endothelial cells, alveolar monocytes/macrophages and neutrophils have been shown to contribute to the generation of toxic reactive oxygen species (ROS) during periods of ischemia and reperfusion and these oxygen-derived free radicals play a major role in precipitating cellular injury and pulmonary damage (de Perrot et al. 2003, supra; Ng et al. 2005, Eur Respir J 25:356-363). During non-hypoxic lung ischemia, as would be present during the initial phase of donor lung storage, pulmonary endothelial cells appear to be a major source of ROS generation due to activation of the NADPH oxidase system via a distinct mechanism that involves mechanotransduction initiated by the lack of vascular flow (Wei et al. 1999, Circ Res 85:682-689). As well as generating ROS that contribute to ischemia-reperfusion injury of lung transplant tissue, gene expression studies using RNA extracted from bronchioalveolar lavage (BAL)-derived cells post transplantation have demonstrated that primary graft dysfunction is associated with the upregulation of multiple genes associated with inflammation, apoptosis, cellular growth and fibrosis (Lande et al. 2007, Proc Am Thorac Soc 4:44-51; Lu et al. 2006, Chest 130:847-854). This process similarly occurs in other types of donor tissues.
Since the pathological consequences of ischemia-reperfusion injury have been identified as the primary cause of graft failure, much recent focus has been on donor lung assessment and handling as a means of preserving function and minimizing subsequent ischemia-reperfusion injury. The development of several lung preservation solutions such as the intracellular type solutions that rely on high K+, low Na+ and the extracellular type solutions (low K+, high Na+), with and without additives such as Dextran 40, glucose and raffinose has allowed for better donor preservation and extension of ischemic times up to 12 hours with excellent donors (de Perrot et al. 2003, supra). As an extension of this preservation process, it has been determined that subtle variations in volume, pressure and temperature of the perfusion solution can also minimize ischemic damage and lead to better outcomes (de Perrot et al. 2003, supra).
A number of other pharmacological strategies targeting the donor tissue either prior to retrieval and/or during storage have been shown to moderate the extent of ischemia-reperfusion injury after both experimental and clinical transplantation. Instillation of exogenous surfactant to donor tissue just prior to retrieval has been shown to have a protective effect (Struber et al. 2007, J Thorac Cardiovasc Surg 133:1620-1625). Immunotargeting of the antioxidant enzyme catalase to the endothelium via conjugation to anti-PECAM antibodies was shown to reduce oxidative stress and subsequent ischemia-reperfusion injury and also prolonged the acceptable cold ischemia storage time of grafts (Kozower et al. 2003, Nat Biotechnol 21:392-398). Inhibition of protease activity by inclusion of the Kunitz type serine protease inhibitor aprotinin to the preservation solution has been shown to attenuate ischemia-reperfusion injury in both animal models (Shimoyama et al. 2005, Eur J Cardiothorac Surg 28:581-587) and in clinical transplantation (Bittner et al. 2006, Eur J Cardiothorac Surg 29:210-215). Addition of a neutrophil elastase inhibitor directly to the preservation solution prior to storage for 16 hours led to reduced ischemia-reperfusion injury and improved tissue function (Mori et al. 2007, Eur J Cardiothorac Surg 32:791-795). Direct addition of the dipeptidyl peptidase (DPP) IV inhibitor AB 192 to the preservation solution prior to storage for 18 hours reduced ischemia-reperfusion injury to the tissue and allowed for successful transplantation (Zhai et al. 2006, Transplant Proc 38:3369-3371). As an alternate approach to reducing tissue damage, Okada et al. (FASEB J 15:2757-2759, 2001) showed that treating donor tissue with an antisense oligonucleotide to block expression of the hypoxia-induced transcription factor Egr-1 inhibited induction of Egr-1 and its downstream target genes such as IL-1β, tissue factor and plasminogen activator inhibitor-1, resulting in marked improvement in graft function and recipient survival. Overall, these previous studies demonstrate that it is technically feasible to pre-treat donor tissue via several pharmacological strategies in order to attempt to mitigate ischemia-reperfusion injury after transplantation.
Nevertheless, although significant advances in donor organ preservation, surgical techniques, immunosuppressive therapies and anti-infective strategies over the last 20 years have been associated with improved graft outcomes in the short to medium term, disappointingly, these have not translated into improved long term outcomes. This is particularly true in the case of lung transplantation where despite often acceptable early lung function being achieved, chronic rejection associated allograft dysfunction, which clinically manifests as Bronchiolitis Obliterans Syndrome (BOS), occurs in 40% of lung transplant recipients (LTR) at 2 years and leads to mortality rates as high as 50% at 5 years (Estenne and Hertz 2002, Am J Respir Crit Care Med 166:440-444; Estenne et al. 2002, J Heart Lung Transplant 21:297-310). BOS is the leading cause of long term mortality in lung transplant recipients and may be significantly contributed to both directly and indirectly by early events related to ischemia-reperfusion injury (Estenne and Hertz 2002, supra; Estenne et al. 2002, supra). Accordingly, there is an ongoing need to develop better methods for the treatment and handling of organs during the harvesting and transplantation process.
In work leading up to the present invention it has been determined that the complex physiological processes which contribute to the onset and progression of graft dysfunction can be retarded by either downregulating the functionality of activin or upregulating follistatin levels.